PDBsum entry 2b55

Transferase

PDB id: 2b55

Contents

Protein chain

276 a.a. *

Ligands

D31

Waters ×104

* Residue conservation analysis

PDB id:

2b55

Name:

Transferase

Title:

Human cyclin dependent kinase 2 (cdk2) complexed with indenopyraxole din-101312

Structure:

Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase, cdk2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.85Å R-factor: 0.213 R-free: 0.256

Authors:

J.Muckelbauer

Key ref:

E.W.Yue et al. (2002). Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3(1,2). J Med Chem, 45, 5233-5248. PubMed id: 12431051 DOI: 10.1021/jm0201722

Date:

27-Sep-05 Release date: 11-Oct-05

Protein chain

P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens

Seq: 298 a.a.

Struc: 276 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm0201722

J Med Chem 45:5233-5248 (2002)

PubMed id: 12431051

Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3(1,2).

E.W.Yue, C.A.Higley, S.V.DiMeo, D.J.Carini, D.A.Nugiel, C.Benware, P.A.Benfield, C.R.Burton, S.Cox, R.H.Grafstrom, D.M.Sharp, L.M.Sisk, J.F.Boylan, J.K.Muckelbauer, A.M.Smallwood, H.Chen, C.H.Chang, S.P.Seitz, G.L.Trainor.

ABSTRACT

The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel and potent compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls. Substitutions at the para position of the phenyl ring at C3 were generally well-tolerated; however, larger groups were generally inactive. For alkyls directly attached to C3, longer chain substituents were not tolerated; however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j, was examined in detail and was determined to have a biological profile consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q, complexed with CDK2 was determined and showed the inhibitor residing in the adenosine 5'-triphosphate pocket of the enzyme.